During the initial funding period, we have identified a cohort of eight rhesus monkeys that are long-term nonprogressors (LTNP) of lentivirus infection. These animals harbor a multiply deleted simian immunodeficiency virus (SIV), in which the axis of Rev and the Rev-responsive element (RRE) had been replaced with the constitutive transport element (CTE) of simian retrovirus type D (SRV/D); CTE was cloned in lieu of nef into the SIVmac239 backbone. The resulting Rev-independent nef-deleted SIV, termed Rev-ind nef~ SIV, critically depends on an intact CTE for viral RNA export into the cytoplasm. Even monkeys infected as neonates have gained tight control over this virus, although this age group is uniquely sensitive to pathogenic effects of viruses that are nonvirulent in adults. As such, Rev-ind nef~ SIV has passed a stringent safety test. The goal of this renewal application is to dissect the host-virus dynamics of this non-pathogenic interaction and to evaluate the efficacy of Rev-ind nef~ SIV to protect the LTNP and monkeys infected for much shorter time periods with this virus against low-dose mucosal challenges with pathogenic SIV. The Specific Aims are to: 1. Examine the host-virus dynamics in rhesus macaques of Indian origin during acute infection with Rev-ind nef~ SIV and wild-type SIVmac239 nef+, during early chronic infection and finally in the LTNP cohort. 2. Assess the efficacy of Rev-ind nef~ SIV against wild-type, pathogenic SIVmac251. We will challenge rhesus monkeys intrarectally with multiple, low-dose inocula of SIVmac251 to more closely mimic the mucosal HIV transmission in humans. 3. Assess the efficacy of Rev-ind nef SIV against heterologous virus challenge with SIVsmE660, again using multiple low-dose intrarectal virus challenges. 4. Elucidate the mechanisms of host control over Rev-ind nef SIV by selective depletion of CD8+ lymphocytes or B cells with cytotoxic monoclonal antibodies. These studies will deepen our understanding of the interaction between the rhesus monkey host, which is susceptible to lentiviral pathogenesis, and Rev-ind nef SIV, an apathogenic virus, even in neonates.